ANSWER
Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells due to environmental changes. Such adaptations can take several forms.
HYPERTROPHY
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Hypertrophy is defined as an increase in cell size that increases the size of the organ. There are no new cells in the hypertrophied organ, only larger cells. The increased cell size is caused by synthesizing more structural components of the cells. Cells that can divide can respond to stress by undergoing hyperplasia (described below) and hypertrophy, whereas nondividing cells (e.g., myocardial fibers) gain tissue mass due to hypertrophy. Hypertrophy and hyperplasia may coexist in many organs and contribute to increased size.
Hypertrophy can be physiologic or pathologic, caused by increased functional demand or hormone and growth factor stimulation. The striated muscle cells in the heart and skeletal muscles have a limited division capacity and respond to increased metabolic demands primarily by hypertrophy. The increased workload is the most common stimulus for muscle hypertrophy. Bodybuilders’ bulging muscles, for example, result from an increase in the size of individual muscle fibers in response to increased demand. The stimulus for hypertrophy in the heart is usually chronic hemodynamic overload caused by hypertension or faulty valves. Muscle cells synthesize more proteins in both tissue types and the number of myofilaments increases.
This increases the force that each myocyte can generate, thereby increasing the muscle’s overall strength and work capacity.
The Hypertrophy Mechanisms
An increase in the production of cellular proteins causes hypertrophy. Heart studies have contributed significantly to our understanding of hypertrophy. Mechanical sensors (activated by increased workload), growth factors (including TGF-, insulin-like growth factor-1 [IGF-1], fibroblast growth factor), and vasoactive agents (such as -adrenergic agonists, endothelin-1, and angiotensin II) can all cause hypertrophy. Mechanical sensors stimulate the production of growth factors and agonists. These stimuli work together to increase the synthesis of muscle proteins, which cause hypertrophy. The phosphoinositide 3-kinase/Akt pathway (postulated to be most important in physiologic, e.g., exercise-induced hypertrophy) and signaling downstream of G protein-coupled receptors (induced by many growth factors and vasoactive agents, and thought to be more important in pathologic hypertrophy) appear to be the two main biochemical pathways involved in muscle hypertrophy. Hypertrophy may also be linked to a change in contractile proteins from adult to fetal or neonatal. During muscle hypertrophy, for example, the isoform of myosin heavy chain is replaced by the isoform, which has a slower, more energy-efficient contraction.
Furthermore, some genes that are only expressed during early development are reexpressed in hypertrophic cells, and their products play a role in the cellular stress response. In the embryonic heart, for example, the atrial natriuretic factor (ANF) gene is expressed in both the atrium and the ventricle, but it is down-regulated after birth. Cardiac hypertrophy, on the other hand, is linked to ANF gene re-expression. ANF is a peptide hormone that causes the kidney to secrete salt, reduces blood volume and pressure, and thus reduces the hemodynamic load.
HYPERPLASIA
Hyperplasia is an increase in the number of cells in an organ or tissue, which usually increases the organ or tissue’s mass. Although hyperplasia and hypertrophy are separate processes, they frequently coexist and may be triggered by the same external stimulus. If the cell population can divide and thus increase the number of cells, hyperplasia occurs. Hyperplasia can be either physiologic or pathologic in nature.
Hyperplasia Physiologica
Physiologic hyperplasia is classified into two types: (1) hormonal hyperplasia, which increases a tissue’s functional capacity when needed, and (2) compensatory hyperplasia, which increases tissue mass following damage or partial resection.
Hormonal hyperplasia is well illustrated by the proliferation of the glandular epithelium of the female breast during puberty and pregnancy, which is usually accompanied by glandular epithelial cell enlargement (hypertrophy). The myth of Prometheus provides a classic illustration of compensatory hyperplasia, demonstrating that the ancient Greeks recognized the liver’s ability to regenerate. Prometheus was chained to a mountain as punishment for stealing the secret of fire from the gods. An eagle devoured his liver daily, only to regenerate every Carlos S. – Adaptations of Cellular Growth and Differentiation night. When people donate one lobe of their liver for transplantation, the remaining cells proliferate, and the organ returns to its original size. Experimental models of partial hepatectomy have been extremely useful in defining the mechanisms that stimulate liver regeneration.
Hyperplasia Pathologic
Excess hormones or growth factors acting on target cells cause the majority of pathologic hyperplasias.
An example of abnormal hormone-induced hyperplasia is endometrial hyperplasia. After a menstrual period, the epithelium undergoes rapid proliferative activity stimulated by pituitary hormones and ovarian estrogen. Rising progesterone levels halt it, usually occurring 10 to 14 days before the end of the menstrual period. However, in some cases, the balance of estrogen and progesterone is disrupted. This causes absolute or relative increases in the amount of estrogen, resulting in endometrial hyperplasia. Pathologic hyperplasia of the uterus is a common cause of abnormal menstrual bleeding. Another common example of pathologic hyperplasia caused by hormone responses, in this case, androgens, is benign prostatic hyperplasia. Although these types of hyperplasia are abnormal, the process is still under control because there are no mutations in genes that control cell division. The hyperplasia regresses when the hormonal stimulation is removed. Because of genetic mutations, the growth control mechanisms in cancer become dysregulated or ineffective, resulting in unrestrained proliferation. Thus, hyperplasia is distinct from cancer, but pathologic hyperplasia creates a fertile environment for cancerous proliferation. Patients with endometrial hyperplasia, for example, are more likely to develop endometrial cancer.
Hyperplasia is a common response to certain viral infections, such as papillomaviruses, which cause skin warts and mucosal lesions composed of hyperplastic epithelium masses. In this case, growth factors produced by viral genes or infected cells may stimulate cellular proliferation.
The Causes of Hyperplasia
Hyperplasia is caused by the proliferation of mature cells stimulated by growth factors and, in some cases, by an increase in the output of new cells from tissue stem cells. For example, after a partial hepatectomy, the liver produces growth factors that bind to receptors on surviving cells and activate signaling pathways that promote cell proliferation. However, if the proliferative capacity of the liver cells is impaired, as in some forms of hepatitis that cause cell injury, hepatocytes can regenerate from intrahepatic stem cells instead.
ATROPHY is a reduction in an organ or tissue size caused by a decrease in cell size and number. Atrophies can be physiologic or pathologic in nature. Physiologic atrophy frequently occurs during normal development. Some embryonic structures, such as the notochord and thyroglossal duct, during fetal development, atrophy. The uterus shrinks in size shortly after parturition, a condition known as physiologic atrophy.
Pathologic atrophy can be localized or generalized, depending on the underlying cause. The following are the most common causes of atrophy:
1. Reduced workload (atrophy of disuse). Skeletal muscle atrophy occurs quickly when a fractured bone is immobilized in a plaster cast or when a patient is restricted to complete bed rest. Once the activity is resumed, the initial decrease in cell size is reversible. Skeletal muscle fibers decrease in number (due to apoptosis) as well as size with increased disuse; this atrophy can be accompanied by increased bone resorption, leading to disuse osteoporosis.
2. Innervation loss (denervation atrophy). Skeletal muscle metabolism and function are both dependent on nerve supply. Nerve damage causes the atrophy of the muscle fibers supplied by those nerves.
3. Reduced blood supply. A decrease in blood supply to a tissue (ischemia) caused by slowly developing arterial occlusive disease results in tissue atrophy. The brain may experience progressive atrophy in late adulthood owing to reduced blood supply caused by atherosclerosis. This is known as senile atrophy, and it also affects the heart.
4. A need for nutrition. The use of skeletal muscle as a source of energy after other reserves, such as fatty stores, has been depleted is associated with severe protein-calorie malnutrition (marasmus). This causes significant muscle wasting (cachexia). Cachexia is also seen in patients with chronic inflammatory diseases and cancer, according to Carlos S. – Cellular Growth and Differentiation. Chronic overproduction of the inflammatory cytokine tumor necrosis factor (TNF) is thought to be responsible for appetite suppression and lipid depletion, ultimately leading to muscle atrophy in the former.
5. Decreased endocrine stimulation. Many hormone-responsive tissues, such as the breast and reproductive organs, rely on endocrine stimulation to function normally. After menopause, the loss of estrogen stimulation causes physiologic atrophy of the endometrium, vaginal epithelium, and breast.
6. Stress. Atrophy can result from tissue compression for any length of time. A benign tumor that grows in size can cause atrophy in the surrounding uninvolved tissues. In this case, atrophy is most likely the result of ischemic changes caused by the expanding mass’s pressure on the blood supply.
Mechanisms of Aging:
Cell atrophy is caused by decreased protein synthesis and increased protein degradation. Protein synthesis decreases as metabolic activity decreases. The ubiquitin-proteasome pathway is primarily responsible for the degradation of cellular proteins. Nutrient deficiency and inactivity can activate ubiquitin ligases, which bind the small peptide ubiquitin to cellular proteins and target them for degradation in proteasomes. This pathway is also thought responsible for the accelerated proteolysis seen in several catabolic conditions, such as cancer cachexia.
In many cases, atrophy is accompanied by increased autophagy, which increases the number of autophagic vacuoles. Autophagy is when a starved cell eats its components to find nutrients and survive. Autophagic vacuoles are membrane-bound vacuoles that contain cell component fragments. Vacuoles eventually fusion with lysosomes, and their contents are digested by lysosomal enzymes.
Some cell debris within autophagic vacuoles may resist digestion and persist as membrane-bound residual bodies in the cytoplasm, acting as a coffin. Lipofuscin granules discussed later in the chapter are an example of such residual bodies. When present in sufficient quantities, they cause the tissue to turn brown (brown atrophy). Autophagy is linked to various types of cell injury, which we will discuss in more detail later.
METAPLASIA
A reversible change in which another cell type replaces one differentiated cell type (epithelial or mesenchymal) is known as metaplasia. It could be an adaptive substitution of cells sensitive to stress for cell types more resistant to the adverse environment.
The most common epithelial metaplasia is columnar to squamous, as occurs in the respiratory tract in response to \schronic irritation. In the chronic cigarette smoker, the normal ciliated columnar epithelial cells of the trachea and \sbronchi are often replaced by stratified squamous epithelial cells. Stones in the excretory ducts of the salivary glands, \spancreas, or bile ducts may also cause replacement of the normal secretory columnar epithelium by stratified \ssquamous epithelium. Vitamin A (retinoic acid) deficiency causes squamous metaplasia in the respiratory epithelium. In all of these cases, the more rugged stratified squamous epithelium survives under conditions that would have killed the more fragile specialized columnar epithelium. However, the transition to metaplastic squamous cells comes at a cost. Although the epithelial lining of the respiratory tract becomes tough, important anti-infection mechanisms such as mucus secretion and columnar epithelial ciliary action are lost. Thus, epithelial metaplasia is a two-edged sword representing a negative change in most cases. Furthermore, if the factors predisposing to metaplasia persist, the metaplastic epithelium may undergo malignant transformation. Thus, squamous cells, which arise in areas of metaplasia of the normal columnar epithelium into squamous epithelium, are a common type of cancer in the respiratory tract.
Metaplasia Mechanisms:
Metaplasia is caused by the reprogramming of stem cells found in normal tissues or undifferentiated mesenchymal cells found in connective tissue rather than a change in the phenotype of an already differentiated cell type. These precursor cells differentiate along a new pathway during a metaplastic change. Signals generated by cytokines, growth factors, and extracellular matrix components in the cells’ environment cause stem cell differentiation to a specific lineage. External stimuli stimulate the expression of genes that direct cells along a specific differentiation pathway. When it comes to vitamins,
Carlos S. – Cellular Growth and Differentiation Adaptations
Retinoic acid, whether in deficiency or excess, is known to regulate gene transcription directly via nuclear retinoid receptors, which can influence the differentiation of progenitors derived from tissue stem cells. It is unknown how other external stimuli cause metaplasia, but it is clear that they, too, alter the activity of transcription factors that regulate differentiation.
QUESTION
Which form of cellular adaptation occurs because of decreased work demands on the cell? Explain your answer.

A. Hypertrophy

B. Hyperplasia

C. Atrophy

D. Metaplasia
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